Swelling‐activated ion channels: functional regulation in cell‐swelling, proliferation and apoptosis

Abstract

Cell volume regulation is one of the most fundamental homeostatic mechanisms and essential for normal cellular function. At the same time, however, many physiological mechanisms are associated with regulatory changes in cell size meaning that the set point for cell volume regulation is under physiological control. Thus, cell volume is under a tight and dynamic control and abnormal cell volume regulation will ultimately lead to severe cellular dysfunction, including alterations in cell proliferation and cell death. This review describes the different swelling-activated ion channels that participate as key players in the maintenance of normal steady-state cell volume, with particular emphasis on the intracellular signalling pathways responsible for their regulation during hypotonic stress, cell proliferation and apoptosis.

TMEM16 Proteins Produce Volume-regulated Chloride Currents That Are Reduced in Mice Lacking TMEM16A

“…Early work suggested intracellular Ca 2ϩ as an important mediator for activation of I Cl,swell and volume-regulated K ϩ channels (5), whereas subsequent studies only found a permissive role of Ca 2ϩ for activation of I Cl,swell (6), reviewed in Ref. 1. In addition, a plethora of factors and signaling pathways have been implicated in activation of I Cl,swell , making cell volume regulation an extremely complex process (reviewed in Refs.…”

Calcium-Activated Potassium Channel KCa3.1 in Lung Dendritic Cell Migration

“…In addition, KCa3.1 is responsible for concerting with calcium oscillation in migratory cells by acting in a fluctuating pattern to keep pace with cell protrusion and retraction (34). KCa3.1 is also a swelling-activated potassium channel in many cell types, and the activation of KCa3.1 can orchestrate the volume, regulate cytoskeleton organization, and facilitate transmembrane water transport (35,36). However, sustained opening of KCa3.1 disrupts the coupling between calcium influx and the calcium-activated potassium channel and thus impairs the temporal dynamics of the calcium signal necessary for cell migration.…”

Two conventional protein kinase C isoforms, α and βI, are involved in the ATP‐induced activation of volume‐regulated anion channel and glutamate release in cultured astrocytes

“…VRACs are also functionally important for cell proliferation and apoptosis. In the case of proliferation, augmented VRAC activity is generally associated with progression via different stages of cell cycle, while in apoptosis VRACs are paradoxically activated in nonswollen cells and play a part in apoptotic cell shrinkage (reviewed in Lang et al 2000;Okada et al 2001;Stutzin and Hoffmann 2006). In astrocytes, ATP stimulates proliferation via the mechanism involving P2Y receptors and PKC (Neary et al 1999).…”

“…Release of inorganic and organic osmolytes via VRAC, in conjunction with K + release via swelling activated K + channels, mediates the reduction of intracellular osmolarity and regulatory cell volume decrease (Lang et al 1998;Mongin and Orlov 2001;Nilius and Droogmans 2003). In addition to cell volume regulation, VRACs are also thought to participate in cell proliferation, apoptosis, modulation of vascular tone, and regulation of membrane potential in various cell types (Okada et al 2001;Nilius and Droogmans 2003;Stutzin and Hoffmann 2006).…”